The growth of prostate cancer (CaP) depends upon the presence of androgen (male) hormones, acting via androgen receptors contained in the cell's nucleus. The only effective, albeit temporary, therapy of prostate cancer is based upon interference of male hormone production or activity, using estrogenic steroids or non-steroidal substances to block the cancer cells' androgen receptors. There are a number of problems with these therapies. Steroidal estrogens had to be abandoned due to their high cardiovascular toxicity. The only steroidal compound clinically used today is cyproterone acetate. However, it also binds to the glucocorticoid and progestin receptors. Current, clinically-used non-steroidal anti-androgens such as Flutamide, Casodex or Anandron do not bind sufficiently to androgen receptors to achieve their complete blockage. None of the current anti-androgens provide permanent relief. It is suspected that the incomplete blockage of the receptors may be the reason why, with time, the therapy invariably becomes ineffective as the CaP cells mutate having proliferated metastatically. At that phase, the cells cannot be substantially influenced by any known chemotherapy or radiation.
There is the further consideration that the current armamentarium for the diagnostic staging of prostate cancer is extremely poor and yet essential in choosing the therapeutic mode. Proof of metastatic dissemination beyond the prostate excludes surgery and relegates these patients to systemic therapy. With improved diagnostic staging, unnecessary prostatectomies, a major and potentially mutilating surgery, could be avoided.
Only recently, an assay has become available for the detection of CaP cells circulating in the blood. However, that finding alone does not imply the existence of metastases. Typically, early metastases occur in the lymph nodes and the later ones develop in the bones. While .sup.99 Tc scans can visualize bone defects, the lymph node metastases are extremely difficult to locate since typically, the infiltrated nodes are neither enlarged nor show changes on either magnetic resonance or x-ray computed tomography. Further, because of their low metabolic rate, the pathological nodes cannot be identified by positron emission spectrography using .sup.18 F-deoxyglucose. Lymph node biopsy is possible only in the pelvic area. Early metastases in inaccessible paraaortic lymph nodes cannot be detected and consequently these patients are operated upon needlessly. Recently developed radiolabeled monoclonal antibodies against prostate cancer have only a limited use due to their low target specificity and long persistence in the blood pool, liver and spleen, which interferes with the imaging.
There have been a number of attempts to develop a CaP radionuclide scanning agent. Several radioiodinated androgen steroids were made, but they suffer from synthetic complexity. Steroidal androgens labeled with .sup.18 F were synthesized as a potential PET imaging agent for prostate cancer, but their practicability is limited due to the complicated synthesis and need for specialized rare equipment (PET scanners) to detect positron emitting radionuclides. There is a further consideration that androgens promote CaP growth.
There is, therefore, substantial interest in developing novel compounds which can provide for the diagnosis and therapy of prostate cancer.
Relevant Literature
N-aryl substituted imidazolinediones have been reported in DE32 22 523; Offenlegungsschrift 26 49 925; WO88/03404; EP0 436426; EP0 494819; EP0 580459, and Teutsch, J. Steroid Biochem. Molec. Biol. (1994) 48:111-119. The activity of the trifluoromethyl, nitro- and trifluoromethyl, cyanophenyl derivatives as high-affinity ligands for the androgen receptor are reported in Teutsch, supra., as well as in many of the foregoing patents.